Most drugs which humans abuse serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug-seeking and drug-taking behavior in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. Currently, studies are focusing on methamphetamine, nicotine and delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana. Numerous attempts to obtain reliable self-administration behavior by laboratory animals with THC have been unsuccessful. In contrast, self-administration behavior has been successfully demonstrated in laboratory animals for almost all other psychoactive drugs abused by humans. From these studies it would seem that marijuana has less potential for abuse than other drugs abused by humans. In previous experiments, we demonstrated persistent intravenous self-administration behavior by squirrel monkeys for doses of THC comparable to those in marijuana smoke inhaled by humans (Tanda et al., Nature Neurosci. 2000, 3, 1073). We have now studied THC self-administration by squirrel monkeys under more complex, second-order schedules of intravenous drug injection. Self-administration behavior of squirrel monkeys was persistently maintained by low intravenous doses of THC under a second-order schedule where drug-seeking responses (lever presses) during the session produced only brief light stimuli that were then paired with THC injection at the end of each daily session. Responding was markedly reduced by substitution of vehicle for THC injections, by presession treatment with the CB1 receptor antagonist SR141716A, and by removal of the brief, drug-paired stimulus presentations during the session. During vehicle-extinction sessions with no brief stimulus presentations, when drug-seeking responses seldom occurred, the repeated reintroduction of brief-stimulus presentations as well as intravenous administration of THC before the start of the session induced a marked reinstatement of drug-seeking behavior. In other studies we are exploring the role of histamine H3 receptors in the modulation of the reinforcing and neurochemical acftions of methamphetamine. Histamine H3 receptors were initially characterized as autoreceptors on histaminergic neurons1, but have now been shown to be widely distributed as presynaptic heteroreceptors on non-histaminergic neurons, whose activation inhibits synthesis and release of other neurotransmitters. We have now shown that blockade of histamine H3 receptors by the selective antagonists thioperamide or clobenpropit potentiates elevations in extracellular dopamine in the shell of the nucleus accumbens induced by methamphetamine, a dopamine releaser, which also releases histamine. We have also shown that histamine H3 receptor blockade by thioperamide or clobenpropit potentiates the rewarding effects of methamphetamine, as measured by self-administration behavior of rats, and the subjective effects of methamphetamine, as measured by drug-discrimination behavior of rats. In a related series of studies, the role of different neurotransmitter systems in the reinforcing and cardiovascular effects of methamphetamine is being evaluated in rats and squirrel monkeys. We previously reported that rats that actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D2 autoreceptor levels in the ventral tegmental area and median and dorsal part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D1 receptors in the shell of the nucleus accumbens. Using in vitro quantitative autoradiography to determine densities of dopamine uptake sites and dopamine D1 and D2 receptors in different brain regions we now have made determinations following 7- and 30-day periods of withdrawal from chronic methamphetamine self-administration. No changes in dopamine dopamine receptor numbers were detected in any brain region examined in rats self-administering methamphetamine compared with littermates receiving yoked infusions of either methamphetamine or saline. Thus, neuroadaptive changes in densities of dopamine receptors in selected brain areas which we observed in our initial study, may contribute to the reinforcing effects of methamphetamine during the acquisition and maintenance phases of self-administration, but they do not appear to contribute to the long-lasting neuroadaptive effects of chronic methamphetamine self-administration which may trigger craving and relapse. In experiments involving complex schedules of drug self-administration, we have shown that stimulus control can be readily established in a manner similar to non-drug reinforcers. We have also shown that punishment can suppress drug self-administration with priming injections reinstating that responding in a manner similar to that seen following extinction.